Heart–lung transplant is the last option for patients with congenital heart disease (CHD) and irreversible pulmonary vascular obstructive disease when the patients are symptomatic despite optimal medical management. In this review, we discuss the clinical issues, management strategies, and pretransplant workup of one such patient.

Clinical Vignette

18-year-old Mr. S, was a full term, healthy neonate without any perinatal issues. He became symptomatic with onset of fast breathing, feeding difficulty, failure to thrive, and recurrent respiratory infections in early infancy. At 6 months of age, he was detected to have persistent low oxygen saturation during an admission for lower respiratory tract infection. On evaluation, he was diagnosed with a cyanotic CHD-double outlet right ventricle, mitral atresia, hypoplastic left ventricle, nonrestrictive ventricular septal defect, restrictive interatrial communication, severe pulmonary artery hypertension (PAH), and pulmonary venous hypertension. He underwent percutaneous balloon atrial septostomy (BAS) at 1 year of age, following which he symptomatically improved and started gaining weight. Child remained on irregular follow-up and was brought to our center for the first time at 5 years of age.

He was thoroughly evaluated. Cardiac catheterization revealed systemic pulmonary artery (PA) pressures, aortic saturation of 83%, and calculated pulmonary vascular resistance index (PVRI) of 6.2 WU.m2. Because of the unfavorable systemic saturation, he was deemed unsuitable for PA banding. Due to severe PAH and single functioning systemic right ventricle, gradually ventricular dysfunction set in. He had a progressive downhill course with symptoms of cough, breathlessness, easy fatigability, orthopnea, and edema, needing repeated hospitalizations every 3–4 months. During each admission, he required intravenous diuretics, inotropes (dobutamine and dopamine), vasodilators (nitroglycerine), oxygen, and antibiotics for stabilization.

At the age of 16 years, he underwent BAS again in view of restrictive interatrial communication [Table 1], but the symptoms did not improve significantly. He was continued on multiple medications, which included pulmonary vasodilators (bosentan and sildenafil), angiotensin-converting enzyme (ACE) inhibitor, diuretics and digoxin, along with salt and water restriction. Despite maximal tolerable medical therapy, he remained in the WHO functional class (FC) III with intermittent deterioration to Class IV. Hence, after extensive counseling and discussion with family, he was planned for heart–lung transplant. His pretransplant workup included multiple blood and radiological investigations and functional assessments following which he was listed for heart–lung transplant. His chest radiograph, 12-lead electrocardiogram and echocardiogram are shown in [Figure 1]. He is still awaiting heart–lung transplant.

Table 1: Cardiac catheterization hemodynamic data at the time of balloon atrial septostomy depicting pressure gradient between the left and the right atrium due to patent foramen ovale restriction

Figure 1: (a) Electrocardiogram of the patient depicting right atrial enlargement, right ventricular dominance and hypertrophy with left axis deviation. (b) Chest radiograph, Postero-anterior view showing cardiomegaly with right atrial enlargement, right ventricular type apex, malposed great vessels, and pruning of peripheral vascularity in lung fields. Skeletal deformity in form of scoliosis is also seen. (c) Echocardiographic image in apical four chamber view showing mitral valve atresia, dilated right atrium and right ventricle.

Question: When should PAH-targeted therapy be started in patients with Eisenmenger's syndrome (ES)?

Answer: Initiation of PAH-targeted therapy is strongly recommended in patients with the WHO FC III. Evidence is stronger for the use of endothelin receptor antagonists (ERAs) than phosphodiesterase-5 (PDE-5) inhibitors.[1],[2],[3],[4],[5],[6],[7] There is lack of evidence for the use of PAH-targeted therapy in ES patients in FC II and is hence not routinely recommended. Patients with ES in FC II should be assessed for the presence of adverse prognostic features, including brain natriuretic peptide levels, C-reactive protein levels, and 6-min walk distance which may support initiation of PAH-targeted therapy.[8],[9],[10]

Question: Which one of the two, ERA/PDE-5 inhibitors, should we start with? When should the 2nd drug be added? Is there any role of upfront combination therapy?

Answer: The choice of initial therapy is influenced by factors such as side effects, interactions, and contraindications. Routine upfront or early sequential oral combination therapy is not supported by the existing literature in patients with ES, unlike in idiopathic pulmonary hypertension. Combination therapy with an ERA and PDE-5 inhibitors should be considered in patients with markers of adverse outcome or clinical deterioration while on monotherapy.[11],[12],[13] Annual influenza and pneumococcal vaccination are also recommended.

Question: What causes hemoptysis in patients with ES?

Answer: The causes of hemoptysis in ES include aortopulmonary collaterals, pulmonary thrombosis, pulmonary tuberculosis, and pulmonary artery (PA) dissection. Approximately 40% of patients develop hemoptysis and treating the cause results in symptom remission in 45% of the cases. Hence, computerized tomographic pulmonary angiography is recommended in an ES patient presenting with hemoptysis.[14],[15]

Question: What is the role of anticoagulation? What should be the target international normalized ratio (INR)?

Answer: Endothelial dysfunction and an imbalance between procoagulant and anti-thrombotic factors results in thrombotic vasculopathy in ES patients. Almost 20% of ES patients have PA thrombus.[16] Anticoagulation should be started in ES patients with atrial fibrillation, pulmonary or systemic thromboembolism and those in congestive heart failure due to significant ventricular dysfunction. It should be continued in patients who do not have significant hemoptysis or other bleeding risks.[17] Target INR should be around 2.5 depending on the risk factors. It does not provide any survival benefit in those without risk factors for thrombosis.[18]

Question: What is the role of beta-blockers? Which beta-blocker should be preferred?

Answer: Literature regarding the use of beta-blockers in ES is scarce. They help to control the heart rate and improve ventricular filling in the setting of diastolic dysfunction. Beta-blockers have a role in recurrent arrhythmia prevention. They may also help in better ventricular remodeling. However, their use in the acutely symptomatic phase results in significant hemodynamic worsening in patients with ES. The preferred beta-blocker for use may be carvedilol.[19],[20]

Question: Are ACE inhibitors useful or harmful?

Answer: In earlier days, ACE inhibitors used to be avoided, anticipating the risk of fall in systemic vascular resistance (SVR) and thus an increase in physiological right to left shunt, resulting in worsening of cyanosis in ES patients. Literature supporting their use is scanty. In a small study, ACE inhibitors were found to improve systemic output, mixed venous saturation, cyanosis, and FC in adult patients with cyanotic CHD.[21]

Question: Is there a role of digoxin in managing such patients?

Answer: Digoxin has been used in ES patients for a long time without sufficient evidence. It may worsen the symptoms of the patient.[22] The current role for digoxin is limited to patients with congestive heart failure and in the presence of atrial fibrillation.

Question: Any role of home oxygen therapy?

Answer: Existing literature does not support the routine prescription of home oxygen therapy. Its use should be individualized and continued only if there is clear benefit to the patient.[23],[24]

Question: What is the best method for assessing iron deficiency in these patients?

Answer: Approximately one-third of ES patients suffer from iron deficiency which is due to reduced absorption and increased consumption of iron from erythrocytosis and chronic bleeding. Transferrin saturation and serum ferritin are the most commonly used parameters to assess iron status.[13],[25]

Question: When should we consider venesection/partial exchange transfusion in these patients?

Answer: Routine venesection in ES patients is contraindicated due to an increased risk of cerebrovascular events. The only indication for venesection is the presence of neurological symptoms of hyperviscosity in iron-replete patients with high hematocrit (>0.65) after ruling out dehydration and cerebral abscess.[13],[26]

Question: What are the risks of noncardiac surgery in these patients? How to manage these patients in the perioperative period?

Answer: Perioperative risks of cardiac surgery in ES patients include increased cyanosis due to decrease in SVR, increased risk of developing arrhythmias, bleeding, and thromboembolic complications. There is a mortality risk of 3.5%–18%, with the risk being higher in emergency and prolonged surgeries. The predictors of outcome include the degree of exercise intolerance, severity of pulmonary hypertension, and requirement for inotropic support. Risk reduction strategies include minimizing blood loss, avoidance of sudden reduction in SVR or rise in PVR, and minimizing the negative cardiovascular effects of positive airway pressure support. PAH-targeted therapies should be continued. The use of vasopressor agents to maintain SVR and intravenous prostanoids to reduce PVR may be considered in the perioperative period.[27],[28] Air embolism should be avoided using air filters.

Question: What are the criteria for listing for heart–lung transplant?

Answer: Patient should be in INTERMACS Class III or less to be listed for transplant.

Question: Is heart–lung transplantation a better strategy than lung transplantation with repair of cardiac defect?

Answer: There is limited literature comprising small numbers comparing the two strategies. Waddell et al. analyzed the United Network for Organ Sharing/International Society for Heart–Lung Transplantation joint transplant registry comparing the two strategies in 605 patients with ES. Combined heart and lung transplantation appeared to be the safer procedure, with a significantly higher survival rate in comparison to lung transplantation with intracardiac repair (P = 0.002).[30] The procedure of choice for ES patients with ventricular septal defect, complex anatomy, or significant left or right ventricular dysfunction remains heart–lung transplantation. The polarity of opinion persists in this area because of the genuine issue of donor organ availability. ES patients with simple cardiac anomalies such as atrial septal defect and patent ductus arteriosus can be treated with a combination of lung transplantation and cardiac repair unless precluded by severe ventricular dysfunction.[31]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgments

The authors would like to thank Prof. S.S. Kothari for constructive suggestions.